Labyrinthine Fluid Signal Intensity on T2-Weighted MR Imaging in Patients With Vestibular Schwannomas Undergoing Proton Radiotherapy: A Longitudinal Assessment.

OBJECTIVE: In vestibular schwannoma patients, a loss of signal intensity (SI) on T2-weighted magnetic resonance imaging (MRI) has been reported within the ipsilateral labyrinth. The purpose of this study was to quantitatively evaluate the occurrence and course of this intensity loss in relation to proton radiotherapy and its possible association with hearing loss. STUDY DESIGN: Retrospective chart review. SETTING: Tertiary referral center. PATIENTS: Patients who received proton therapy for a vestibular schwannoma and underwent at least two high-resolution T2-weighted cisternographic sequence (constructive interference in steady state/fast imaging employing steady-state acquisition/DRIVE) MRIs and audiometry assessments. MAIN OUTCOME MEASURES: Relative T2 SIs from the vestibules and basal/apical cochlear turns of the labyrinth, bilaterally. RESULTS: Ninety-five MRI scans from 34 patients were included. The apical turn of the ipsilateral cochlea showed a lower mean cochlear SI than on the contralateral side (±3.5 versus 5.0). The mean relative cochlear SI did not significantly change after proton radiotherapy. The ipsilateral vestibule showed a higher SI than the cochlea. The relative mean cochlear SI was not directly correlated to (the degree of) hearing loss before or after proton radiotherapy, nor did it predict future hearing loss. CONCLUSION: The relative mean cochlear SI on cisternographic T2-MRI in vestibular schwannoma patients is diminished on the treated side, when compared with the ipsilateral vestibule and the contralateral cochlea/vestibule. The SI of the ipsilateral cochlea does not further decrease after proton radiotherapy and seems to be related to the tumor rather than the therapy. The diminished cochlear SI does not correlate with subsequent loss of hearing.

Graded Prognostic Assessment (GPA) for Patients With Lung Cancer and Brain Metastases: Initial Report of the Small Cell Lung Cancer GPA and Update of the Non-Small Cell Lung Cancer GPA Including the Effect of Programmed Death Ligand 1 and Other Prognostic Factors.

PURPOSE: Patients with lung cancer and brain metastases represent a markedly heterogeneous population. Accurate prognosis is essential to optimally individualize care. In prior publications, we described the graded prognostic assessment (GPA), but a GPA for patients with small cell lung cancer (SCLC) has never been reported, and in non-small cell lung cancer (NSCLC), the effect of programmed death ligand 1 (PD-L1) was unknown. The 3-fold purpose of this work is to provide the initial report of an SCLC GPA, to evaluate the effect of PD-L1 on survival in patients with NSCLC, and to update the Lung GPA accordingly. METHODS AND MATERIALS: A multivariable analysis of prognostic factors and treatments associated with survival was performed on 4183 patients with lung cancer (3002 adenocarcinoma, 611 nonadenocarcinoma, 570 SCLC) with newly diagnosed brain metastases between January 1, 2015, and December 31, 2020, using a multi-institutional retrospective database. Significant variables were used to update the Lung GPA. RESULTS: Overall median survival for lung adenocarcinoma, SCLC, and nonadenocarcinoma was 17, 10, and 8 months, respectively, but varied widely by GPA from 2 to 52 months. In SCLC, the significant prognostic factors were age, performance status, extracranial metastases, and number of brain metastases. In NSCLC, the distribution of molecular markers among patients with lung adenocarcinoma and known primary tumor molecular status revealed alterations/expression in PD-L1 50% to 100%, PD-L1 1% to 49%, epidermal growth factor receptor, and anaplastic lymphoma kinase in 32%, 31%, 30%, and 7%, respectively. Median survival of patients with lung adenocarcinoma and brain metastases with 0, 1% to 49%, and ≥50% PD-L1 expression was 17, 19, and 24 months, respectively (P < .01), confirming PD-L1 is a prognostic factor. Previously identified prognostic factors for NSCLC (epidermal growth factor receptor and anaplastic lymphoma kinase status, performance status, age, number of brain metastases, and extracranial metastases) were reaffirmed. These factors were incorporated into the updated Lung GPA with robust separation between subgroups for all histologies. CONCLUSIONS: Survival for patients with lung cancer and brain metastases has improved but varies widely. The initial report of a GPA for SCLC is presented. For patients with NSCLC-adenocarcinoma and brain metastases, PD-L1 is a newly identified significant prognostic factor, and the previously identified factors were reaffirmed. The updated indices establish unique criteria for SCLC, NSCLC-nonadenocarcinoma, and NSCLC-adenocarcinoma (incorporating PD-L1). The updated Lung GPA, available for free at brainmetgpa.com, provides an accurate tool to estimate survival, individualize treatment, and stratify clinical trials.

Survival in Patients With Brain Metastases: Summary Report on the Updated Diagnosis-Specific Graded Prognostic Assessment and Definition of the Eligibility Quotient.

PURPOSE: Conventional wisdom has rendered patients with brain metastases ineligible for clinical trials for fear that poor survival could mask the benefit of otherwise promising treatments. Our group previously published the diagnosis-specific Graded Prognostic Assessment (GPA). Updates with larger contemporary cohorts using molecular markers and newly identified prognostic factors have been published. The purposes of this work are to present all the updated indices in a single report to guide treatment choice, stratify research, and define an eligibility quotient to expand eligibility. METHODS: A multi-institutional database of 6,984 patients with newly diagnosed brain metastases underwent multivariable analyses of prognostic factors and treatments associated with survival for each primary site. Significant factors were used to define the updated GPA. GPAs of 4.0 and 0.0 correlate with the best and worst prognoses, respectively. RESULTS: Significant prognostic factors varied by diagnosis and new prognostic factors were identified. Those factors were incorporated into the updated GPA with robust separation (P < .01) between subgroups. Survival has improved, but varies widely by GPA for patients with non-small-cell lung, breast, melanoma, GI, and renal cancer with brain metastases from 7-47 months, 3-36 months, 5-34 months, 3-17 months, and 4-35 months, respectively. CONCLUSION: Median survival varies widely and our ability to estimate survival for patients with brain metastases has improved. The updated GPA (available free at brainmetgpa.com) provides an accurate tool with which to estimate survival, individualize treatment, and stratify clinical trials. Instead of excluding patients with brain metastases, enrollment should be encouraged and those trials should be stratified by the GPA to ensure those trials make appropriate comparisons. Furthermore, we recommend the expansion of eligibility to allow for the enrollment of patients with previously treated brain metastases who have a 50% or greater probability of an additional year of survival (eligibility quotient > 0.50).

Beyond an Updated Graded Prognostic Assessment (Breast GPA): A Prognostic Index and Trends in Treatment and Survival in Breast Cancer Brain Metastases From 1985 to Today.

PURPOSE: Brain metastases are a common sequelae of breast cancer. Survival varies widely based on diagnosis-specific prognostic factors (PF). We previously published a prognostic index (Graded Prognostic Assessment [GPA]) for patients with breast cancer with brain metastases (BCBM), based on cohort A (1985-2007, n = 642), then updated it, reporting the effect of tumor subtype in cohort B (1993-2010, n = 400). The purpose of this study is to update the Breast GPA with a larger contemporary cohort (C) and compare treatment and survival across the 3 cohorts. METHODS AND MATERIALS: A multi-institutional (19), multinational (3), retrospective database of 2473 patients with breast cancer with newly diagnosed brain metastases (BCBM) diagnosed from January 1, 2006, to December 31, 2017, was created and compared with prior cohorts. Associations of PF and treatment with survival were analyzed. Kaplan-Meier survival estimates were compared with log-rank tests. PF were weighted and the Breast GPA was updated such that a GPA of 0 and 4.0 correlate with the worst and best prognoses, respectively. RESULTS: Median survival (MS) for cohorts A, B, and C improved over time (from 11, to 14 to 16 months, respectively; P < .01), despite the subtype distribution becoming less favorable. PF significant for survival were tumor subtype, Karnofsky Performance Status, age, number of BCBMs, and extracranial metastases (all P < .01). MS for GPA 0 to 1.0, 1.5-2.0, 2.5-3.0, and 3.5-4.0 was 6, 13, 24, and 36 months, respectively. Between cohorts B and C, the proportion of human epidermal receptor 2 + subtype decreased from 31% to 18% (P < .01) and MS in this subtype increased from 18 to 25 months (P < .01). CONCLUSIONS: MS has improved modestly but varies widely by diagnosis-specific PF. New PF are identified and incorporated into an updated Breast GPA (free online calculator available at brainmetgpa.com). The Breast GPA facilitates clinical decision-making and will be useful for stratification of future clinical trials. Furthermore, these data suggest human epidermal receptor 2-targeted therapies improve clinical outcomes in some patients with BCBM.

Radiation Therapy Pain Management: Prevalence of Symptoms and Effectiveness of Treatment Options.

BACKGROUND: The prevalence of pain among patients undergoing radiation therapy (RT) is not well described. OBJECTIVES: The purpose of this study was to assess the prevalence and management of pain in patients undergoing RT. METHODS: 94 patients undergoing RT were surveyed at two time points during the course of their treatment. Patients reported on pain, fatigue, nausea, headache, and depressive symptoms, as well as on the use of pharmacologic and nonpharmacologic or alternative methods for symptom management. FINDINGS: The mean severity of pain did not change significantly between the first week of RT and the final week. Severity of pain was associated with worse fatigue, nausea, headaches, and depressive symptoms, providing opportunities for providers to address multiple co-occurring symptoms. Rates of opioid and marijuana use remained similar between the two time points. More than half of the patients reported use of at least one nonpharmacologic method for pain management, with use increasing during the course of RT.

Estimating survival in patients with gastrointestinal cancers and brain metastases: An update of the graded prognostic assessment for gastrointestinal cancers (GI-GPA).

BACKGROUND: Patients with gastrointestinal cancers and brain metastases (BM) represent a unique and heterogeneous population. Our group previously published the Diagnosis-Specific Graded Prognostic Assessment (DS-GPA) for patients with GI cancers (GI-GPA) (1985-2007, n = 209). The purpose of this study is to update the GI-GPA based on a larger contemporary database. METHODS: An IRB-approved consortium database analysis was performed using a multi-institutional (18), multi-national (3) cohort of 792 patients with gastrointestinal (GI) cancers, with newly-diagnosed BM diagnosed between 1/1/2006 and 12/31/2017. Survival was measured from date of first treatment for BM. Multiple Cox regression was used to select and weight prognostic factors in proportion to their hazard ratios. These factors were incorporated into the updated GI-GPA. RESULTS: Median survival (MS) varied widely by primary site and other prognostic factors. Four significant factors (KPS, age, extracranial metastases and number of BM) were used to formulate the updated GI-GPA. Overall MS for this cohort remains poor; 8 months. MS by GPA was 3, 7, 11 and 17 months for GPA 0-1, 1.5-2, 2.5-3.0 and 3.5-4.0, respectively. >30% present in the worst prognostic group (GI-GPA of ≤1.0). CONCLUSIONS: Brain metastases are not uncommon in GI cancer patients and MS varies widely among them. This updated GI-GPA index improves our ability to estimate survival for these patients and will be useful for therapy selection, end-of-life decision-making and stratification for future clinical trials. A user-friendly, free, on-line app to calculate the GPA score and estimate survival for an individual patient is available at brainmetgpa.com.

Estimating survival for renal cell carcinoma patients with brain metastases: an update of the Renal Graded Prognostic Assessment tool.

Background: Brain metastases are a common complication of renal cell carcinoma (RCC). Our group previously published the Renal Graded Prognostic Assessment (GPA) tool. In our prior RCC study (n = 286, 1985-2005), we found marked heterogeneity and variation in outcomes. In our recent update in a larger, more contemporary cohort, we identified additional significant prognostic factors. The purpose of this study is to update the original Renal-GPA based on the newly identified prognostic factors. Methods: A multi-institutional retrospective institutional review board-approved database of 711 RCC patients with new brain metastases diagnosed from January 1, 2006 to December 31, 2015 was created. Clinical parameters and treatment were correlated with survival. A revised Renal GPA index was designed by weighting the most significant factors in proportion to their hazard ratios and assigning scores such that the patients with the best and worst prognoses would have a GPA of 4.0 and 0.0, respectively. Results: The 4 most significant factors were Karnofsky performance status, number of brain metastases, extracranial metastases, and hemoglobin. The overall median survival was 12 months. Median survival for GPA groups 0-1.0, 1.5-2.0, 2.5-3, and 3.5-4.0 (% n = 25, 27, 30 and 17) was 4, 12, 17, and 35 months, respectively. Conclusion: The updated Renal GPA is a user-friendly tool that will help clinicians and patients better understand prognosis, individualize clinical decision making and treatment selection, provide a means to compare retrospective literature, and provide more robust stratification of future clinical trials in this heterogeneous population. To simplify use of this tool in daily practice, a free online application is available at brainmetgpa.com.

Estimating Survival in Melanoma Patients With Brain Metastases: An Update of the Graded Prognostic Assessment for Melanoma Using Molecular Markers (Melanoma-molGPA).

PURPOSE: To update the Diagnosis-Specific Graded Prognostic Assessment (DS-GPA) for a markedly heterogeneous patient population, patients with melanoma and brain metastases, using a larger, more current cohort, including molecular markers. METHODS: The original Melanoma-GPA is based on data from 483 patients whose conditions were diagnosed between 1985 and 2005. This is a multi-institutional retrospective database analysis of 823 melanoma patients with newly diagnosed brain metastases from January 1, 2006, to December 31, 2015. Multivariable analyses identified significant prognostic factors, which were weighted and included in the updated index (Melanoma-molGPA). Multiple Cox regression was used to select and weight prognostic factors in proportion to their hazard ratios to design the updated Melanoma-molGPA in which scores of 4.0 and 0.0 are associated with the best and worst prognoses, as with all of the diagnosis-specific GPA indices. Log-rank tests were used to compare adjacent classes. RESULTS: There were 5 significant prognostic factors for survival (age, Karnofsky performance status [KPS], extracranial metastases [ECM], number of brain metastases, and BRAF status), whereas only KPS and the number of brain metastases were significant in the original Melanoma-GPA. Median survival improved from 6.7 to 9.8 months between the 2 treatment eras, and the median survival times for patients with Melanoma-molGPA of 0 to 1.0, 1.5 to 2.0, 2.5 to 3.0, and 3.5 to 4.0 were 4.9, 8.3, 15.8, and 34.1 months (P<.0001 between each adjacent group). CONCLUSIONS: Survival and our ability to estimate survival in melanoma patients with brain metastases has improved significantly. The updated Melanoma-molGPA, a user-friendly tool to estimate survival, will facilitate clinical decision making regarding whether and which treatment is appropriate and will also be useful for stratification of future clinical trials. To further simplify use, a free online/smart phone app is available at brainmetgpa.com.

Limitations of analytical dose calculations for small field proton radiosurgery.

The purpose of the work was to evaluate the dosimetric uncertainties of an analytical dose calculation engine and the impact on treatment plans using small fields in intracranial proton stereotactic radiosurgery (PSRS) for a gantry based double scattering system. 50 patients were evaluated including 10 patients for each of 5 diagnostic indications of: arteriovenous malformation (AVM), acoustic neuroma (AN), meningioma (MGM), metastasis (METS), and pituitary adenoma (PIT). Treatment plans followed standard prescription and optimization procedures for PSRS. We performed comparisons between delivered dose distributions, determined by Monte Carlo (MC) simulations, and those calculated with the analytical dose calculation algorithm (ADC) used in our current treatment planning system in terms of dose volume histogram parameters and beam range distributions. Results show that the difference in the dose to 95% of the target (D95) is within 6% when applying measured field size output corrections for AN, MGM, and PIT. However, for AVM and METS, the differences can be as great as 10% and 12%, respectively. Normalizing the MC dose to the ADC dose based on the dose of voxels in a central area of the target reduces the difference of the D95 to within 6% for all sites. The generally applied margin to cover uncertainties in range (3.5% of the prescribed range + 1 mm) is not sufficient to cover the range uncertainty for ADC in all cases, especially for patients with high tissue heterogeneity. The root mean square of the R90 difference, the difference in the position of distal falloff to 90% of the prescribed dose, is affected by several factors, especially the patient geometry heterogeneity, modulation and field diameter. In conclusion, implementation of Monte Carlo dose calculation techniques into the clinic can reduce the uncertainty of the target dose for proton stereotactic radiosurgery. If MC is not available for treatment planning, using MC dose distributions to adjust the delivered doses level can also reduce uncertainties below 3% for mean target dose and 6% for the D95.

Estimating Survival in Patients With Lung Cancer and Brain Metastases: An Update of the Graded Prognostic Assessment for Lung Cancer Using Molecular Markers (Lung-molGPA).

IMPORTANCE: Lung cancer is the leading cause of cancer-related mortality in the United States and worldwide. As systemic therapies improve, patients with lung cancer live longer and thus are at increased risk for brain metastases. Understanding how prognosis varies across this heterogeneous patient population is essential to individualize care and design future clinical trials. OBJECTIVE: To update the current Diagnosis-Specific Graded Prognostic Assessment (DS-GPA) for patients with non-small-cell lung cancer (NSCLC) and brain metastases. The DS-GPA is based on data from patients diagnosed between 1985 and 2005, and we set out to update it by incorporating more recently reported gene and molecular alteration data for patients with NSCLC and brain metastases. This new index is called the Lung-molGPA. DESIGN, SETTING, AND PARTICIPANTS: This is a multi-institutional retrospective database analysis of 2186 patients diagnosed between 2006 and 2014 with NSCLC and newly diagnosed brain metastases. The multivariable analyses took place between December 2015 and May 2016, and all prognostic factors were weighted for significance by hazard ratios. Significant factors were included in the updated Lung-molGPA prognostic index. MAIN OUTCOMES AND MEASURES: The main outcome was survival. Multiple Cox regression was used to select and weight prognostic factors in proportion to their hazard ratios. Log rank tests were used to compare adjacent classes and to compare overall survival for adenocarcinoma vs nonadenocarcinoma groups. RESULTS: The original DS-GPA was based on 4 factors found in 1833 patients with NSCLC and brain metastases diagnosed between 1985 and 2005: patient age, Karnofsky Performance Status, extracranial metastases, and number of brain metastases. The patients studied for the creation of the DS-GPA had a median survival of 7 months from the time of initial treatment of brain metastases. To design the updated Lung-molGPA, we analyzed data from 2186 patients from 2006 through 2014 with NSCLC and newly diagnosed brain metastases (1521 adenocarcinoma and 665 nonadenocarcinoma). Significant prognostic factors included the original 4 factors used in the DS-GPA index plus 2 new factors: EGFR and ALK alterations in patients with adenocarcinoma (mutation status was not routinely tested for nonadenocarcinoma). The overall median survival for the cohort in the present study was 12 months, and those with NSCLC-adenocarcinoma and Lung-molGPA scores of 3.5 to 4.0 had a median survival of nearly 4 years. CONCLUSIONS AND RELEVANCE: In recent years, patient survival and physicians' ability to predict survival in NSCLC with brain metastases has improved significantly. The updated Lung-molGPA incorporating gene alteration data into the DS-GPA is a user-friendly tool that may facilitate clinical decision making and appropriate stratification of future clinical trials.

Mapping (15)O production rate for proton therapy verification.

PURPOSE: This work was a proof-of-principle study for the evaluation of oxygen-15 ((15)O) production as an imaging target through the use of positron emission tomography (PET), to improve verification of proton treatment plans and to study the effects of perfusion. METHODS AND MATERIALS: Dynamic PET measurements of irradiation-produced isotopes were made for a phantom and rabbit thigh muscles. The rabbit muscle was irradiated and imaged under both live and dead conditions. A differential equation was fitted to phantom and in vivo data, yielding estimates of (15)O production and clearance rates, which were compared to live versus dead rates for the rabbit and to Monte Carlo predictions. RESULTS: PET clearance rates agreed with decay constants of the dominant radionuclide species in 3 different phantom materials. In 2 oxygen-rich materials, the ratio of (15)O production rates agreed with the expected ratio. In the dead rabbit thighs, the dynamic PET concentration histories were accurately described using (15)O decay constant, whereas the live thigh activity decayed faster. Most importantly, the (15)O production rates agreed within 2% (P>.5) between conditions. CONCLUSIONS: We developed a new method for quantitative measurement of (15)O production and clearance rates in the period immediately following proton therapy. Measurements in the phantom and rabbits were well described in terms of (15)O production and clearance rates, plus a correction for other isotopes. These proof-of-principle results support the feasibility of detailed verification of proton therapy treatment delivery. In addition, (15)O clearance rates may be useful in monitoring permeability changes due to therapy.

Outcomes of proton therapy for the treatment of uveal metastases.

PURPOSE/OBJECTIVE(S): Radiation therapy can be used to treat uveal metastases with the goal of local control and improvement of quality of life. Proton therapy can be used to treat uveal tumors efficiently and with expectant minimization of normal tissue injury. Here, we report the use of proton beam therapy for the management of uveal metastases. METHODS AND MATERIALS: A retrospective chart review was made of all patients with uveal metastases treated at our institution with proton therapy between June 2002 and June 2012. Patient and tumor characteristics, fractionation and dose schemes, local control, and toxicities are reported. RESULTS: Ninety patients were identified. Of those, 13 were excluded because of missing information. We report on 77 patients with 99 affected eyes with available data. Patients were 68% female, and the most common primary tumor was breast carcinoma (49%). The median age at diagnosis of uveal metastasis was 57.9 years. Serous retinal detachment was seen in 38% of treated eyes. The median follow-up time was 7.7 months. The median dose delivered to either eye was 20 Gy(relative biological effectiveness [RBE]) in 2 fractions. Local control was 94%. The median survival after diagnosis of uveal metastases was 12.3 months (95% confidence interval, 7.7-16.8). Death in all cases was secondary to systemic disease. Radiation vasculopathy, measured decreased visual acuity, or both was observed in 50% of evaluable treated eyes. The actuarial rate of radiation vasculopathy, measured decreased visual acuity, or both was 46% at 6 months and 73% at 1 year. The 6 eyes with documented local failure were successfully salvaged with retreatment. CONCLUSIONS: Proton therapy is an effective and efficient means of treating uveal metastases. Acutely, the majority of patients experience minor adverse effects. For longer-term survivors, the risk of retinal injury with vision loss increases significantly over the first year.

Clinical application of in-room positron emission tomography for in vivo treatment monitoring in proton radiation therapy.

PURPOSE: The purpose of this study is to evaluate the potential of using in-room positron emission tomography (PET) for treatment verification in proton therapy and for deriving suitable PET scan times. METHODS AND MATERIALS: Nine patients undergoing passive scattering proton therapy underwent scanning immediately after treatment with an in-room PET scanner. The scanner was positioned next to the treatment head after treatment. The Monte Carlo (MC) method was used to reproduce PET activities for each patient. To assess the proton beam range uncertainty, we designed a novel concept in which the measured PET activity surface distal to the target at the end of range was compared with MC predictions. The repositioning of patients for the PET scan took, on average, approximately 2 minutes. The PET images were reconstructed considering varying scan times to test the scan time dependency of the method. RESULTS: The measured PET images show overall good spatial correlations with MC predictions. Some discrepancies could be attributed to uncertainties in the local elemental composition and biological washout. For 8 patients treated with a single field, the average range differences between PET measurements and computed tomography (CT) image-based MC results were <5 mm (<3 mm for 6 of 8 patients) and root-mean-square deviations were 4 to 11 mm with PET-CT image co-registration errors of approximately 2 mm. Our results also show that a short-length PET scan of 5 minutes can yield results similar to those of a 20-minute PET scan. CONCLUSIONS: Our first clinical trials in 9 patients using an in-room PET system demonstrated its potential for in vivo treatment monitoring in proton therapy. For a quantitative range prediction with arbitrary shape of target volume, we suggest using the distal PET activity surface.

Simulation of prompt gamma-ray emission during proton radiotherapy.

The measurement of prompt gamma rays emitted from proton-induced nuclear reactions has been proposed as a method to verify in vivo the range of a clinical proton radiotherapy beam. A good understanding of the prompt gamma-ray emission during proton therapy is key to develop a clinically feasible technique, as it can facilitate accurate simulations and uncertainty analysis of gamma detector designs. Also, the gamma production cross-sections may be incorporated as prior knowledge in the reconstruction of the proton range from the measurements. In this work, we performed simulations of proton-induced nuclear reactions with the main elements of human tissue, carbon-12, oxygen-16 and nitrogen-14, using the nuclear reaction models of the GEANT4 and MCNP6 Monte Carlo codes and the dedicated nuclear reaction codes TALYS and EMPIRE. For each code, we made an effort to optimize the input parameters and model selection. The results of the models were compared to available experimental data of discrete gamma line cross-sections. Overall, the dedicated nuclear reaction codes reproduced the experimental data more consistently, while the Monte Carlo codes showed larger discrepancies for a number of gamma lines. The model differences lead to a variation of the total gamma production near the end of the proton range by a factor of about 2. These results indicate a need for additional theoretical and experimental study of proton-induced gamma emission in human tissue.

Summary report on the graded prognostic assessment: an accurate and facile diagnosis-specific tool to estimate survival for patients with brain metastases.

PURPOSE: Our group has previously published the Graded Prognostic Assessment (GPA), a prognostic index for patients with brain metastases. Updates have been published with refinements to create diagnosis-specific Graded Prognostic Assessment indices. The purpose of this report is to present the updated diagnosis-specific GPA indices in a single, unified, user-friendly report to allow ease of access and use by treating physicians. METHODS: A multi-institutional retrospective (1985 to 2007) database of 3,940 patients with newly diagnosed brain metastases underwent univariate and multivariate analyses of prognostic factors associated with outcomes by primary site and treatment. Significant prognostic factors were used to define the diagnosis-specific GPA prognostic indices. A GPA of 4.0 correlates with the best prognosis, whereas a GPA of 0.0 corresponds with the worst prognosis. RESULTS: Significant prognostic factors varied by diagnosis. For lung cancer, prognostic factors were Karnofsky performance score, age, presence of extracranial metastases, and number of brain metastases, confirming the original Lung-GPA. For melanoma and renal cell cancer, prognostic factors were Karnofsky performance score and the number of brain metastases. For breast cancer, prognostic factors were tumor subtype, Karnofsky performance score, and age. For GI cancer, the only prognostic factor was the Karnofsky performance score. The median survival times by GPA score and diagnosis were determined. CONCLUSION: Prognostic factors for patients with brain metastases vary by diagnosis, and for each diagnosis, a robust separation into different GPA scores was discerned, implying considerable heterogeneity in outcome, even within a single tumor type. In summary, these indices and related worksheet provide an accurate and facile diagnosis-specific tool to estimate survival, potentially select appropriate treatment, and stratify clinical trials for patients with brain metastases.

Effect of tumor subtype on survival and the graded prognostic assessment for patients with breast cancer and brain metastases.

PURPOSE: The diagnosis-specific Graded Prognostic Assessment (GPA) was published to clarify prognosis for patients with brain metastases. This study refines the existing Breast-GPA by analyzing a larger cohort and tumor subtype. METHODS AND MATERIALS: A multi-institutional retrospective database of 400 breast cancer patients treated for newly diagnosed brain metastases was generated. Prognostic factors significant for survival were analyzed by multivariate Cox regression and recursive partitioning analysis (RPA). Factors were weighted by the magnitude of their regression coefficients to define the GPA index. RESULTS: Significant prognostic factors by multivariate Cox regression and RPA were Karnofsky performance status (KPS), HER2, ER/PR status, and the interaction between ER/PR and HER2. RPA showed age was significant for patients with KPS 60 to 80. The median survival time (MST) overall was 13.8 months, and for GPA scores of 0 to 1.0, 1.5 to 2.0, 2.5 to 3.0, and 3.5 to 4.0 were 3.4 (n = 23), 7.7 (n = 104), 15.1 (n = 140), and 25.3 (n = 133) months, respectively (p < 0.0001). Among HER2-negative patients, being ER/PR positive improved MST from 6.4 to 9.7 months, whereas in HER2-positive patients, being ER/PR positive improved MST from 17.9 to 20.7 months. The log-rank statistic (predictive power) was 110 for the Breast-GPA vs. 55 for tumor subtype. CONCLUSIONS: The Breast-GPA documents wide variation in prognosis and shows clear separation between subgroups of patients with breast cancer and brain metastases. This tool will aid clinical decision making and stratification in clinical trials. These data confirm the effect of tumor subtype on survival and show the Breast-GPA offers significantly more predictive power than the tumor subtype alone.